The long-term goal of this project is to understand the role of the neurotrophin receptor p75 in neural development and regeneration. Although initially identified for its ability to bind neurotrophins, p75 serves as a critical co-receptor to transduce multiple signaling pathways in neural development and function. For example, it is a co-receptor for glycosyl-phosphophatidyl inositol (GPI)-linked NgR and ephrinA5. We have been using the dorsal root ganglion (DRG) sensory neuron system to understand the role of p75 in neural development. DRG neurons are classified by multiple criteria including sizes, neuropeptides, trophic factor-dependence and sensory modalities. Sensory neuron development has embryonic and postnatal phases and is controlled by both extrinsic and intrinsic factors. We previously showed that 50% of DRG neurons are lost in p75 null mutants at birth. Because p75 is expressed in neurons, Schwann and target cells involved in the development of DRG sensory system, we generated p75 conditional mutant mice via the Cre-LoxP system (p75 floxed mice) to understand the role of p75 in these individual cell types. To delete the p75 gene in neurons, we crossed p75 floxed mice with mice expressing Cre under the control of the Islet1 promoter. In contrast to p75 null mutants, there is no DRG neuronal loss in these conditional mutants at birth. However, 20% of total DRG neurons are lost in adult mutants, including a significant number of glial cell-derived neurotrophic factor (GDNF)-dependent c-Ret+IB4+ nociceptive neurons. GDNF-dependent survival of postnatal p75-deficient DRG neurons is markedly decreased, suggesting that p75 is required for GDNF signaling. Preliminary results showed that p75 and GPI-linked GDNF receptor 11/12 (GFR11) and c-Ret are co-localized on DRG neurons and form a GDNF- dependent complex. Furthermore, p75 increases sensitivity of GDNF-induced MAPK Erk1/2 activation in transfected HEK 293 cells. To further understand the cellular and molecular mechanisms of p75-dependent signaling pathways in neural development, three specific aims are proposed. Aim 1 is to determine the role of p75 in neurons, epithelial and Schwann cells during embryonic spinal sensory neuron development. Aim 2 is to determine the role of p75 in nonpeptidergic neuron development. Aim 3 is to determine the role of p75 in GDNF signaling. PUBLIC HEALTH RELEVANCE: P75 may serve as a co-receptor to integrate multiple signaling pathways to regulate diverse cellular activities and is implicated in multiple human diseases in both peripheral and central nervous systems. The results from the present study will provide insights into designing therapeutic strategies to treat neurodegenerative diseases and peripheral neuropathy, including debilitating Alzheimer's Disease and chronic pain.